Project Grant R44CA272078

XOLACTA: AN ADJUVANT THERAPY FOR TREATMENT OF RADIATION SIDE EFFECTS DURING HER2-POSITIVE BREAST CANCER TREATMENT - PROJECT SUMMARY/ABSTRACT TINY CARGO HAS DEVELOPED A NOVEL THERAPEUTIC CALLED XOLACTATM COMPRISED OF MILK EXTRACELLULAR VESICLES (MEVS) LOADED WITH A DRUG THAT PROMOTES REGENERATIVE HEALING WHEN GIVEN FOLLOWING EXPOSURE TO IONIZING RADIATION. WE ARE SEEKING TO ADVANCE XOLACTA AS A RADIOTHERAPEUTIC ADJUVANT TREATMENT DURING RADIATION THERAPY (RT)-A THERAPEUTIC APPROACH STUDIED UNDER OUR PHASE I AWARD (R41 CA272078-01A1). WE HAVE ALSO MET WITH THE FDA (PIND#167551) AND GAINED ENTRY TO THE ANIMAL RULE IN EFFORTS TO UTILIZE XOLACTA AS DUAL-USE RADIOTHERAPEUTIC MEDICAL COUNTERMEASURE. OUR PATENT PORTFOLIO INCLUDES AN EXCLUSIVE LICENSE FROM VIRGINIA TECH ON PENDING PATENTS WITH CONFIRMED FTO FOR: 1) METHODS FOR INDUSTRIAL PURIFICATION OF MEVS FROM MILK; 2) COMPOSITIONS AND METHODS FOR MEV LOADING NECESSARY FOR PREPARATION OF XOLACTA; 3) METHODS FOR NON-COLD CHAIN STORAGE OF XOLACTA; 4) METHODS FOR ENHANCING MEV TARGETING AND UPTAKE IN IRRADIATED TISSUES; AND 5) METHODS FOR USE OF XOLACTA AS AN ORALLY AVAILABLE RADIOTHERAPEUTIC. WE ARE CONSTRUCTING AN INDUSTRIAL FACILITY IN ROANOKE, VA THAT WILL PRODUCE DOZENS OF LITERS OF XOLACTA WEEKLY STARTING Q1/Q2 2025, WHICH WILL PROVIDE AMPLE VOLUME FOR LARGE STUDIES SUCH AS THOSE PROPOSED HEREIN, AS WELL AS PK/ADME STUDIES WE ARE UNDERTAKING WITH THE ARMED FORCES RADIOBIOLOGY RESEARCH INSTITUTE, OR AFRRI. PERHAPS MOST NOTABLY, WE HAVE BROKEN COLD-CHAIN RELIANCE BY ENABLING LYOPHILIZATION OF XOLACTA, AN ACCOMPLISHMENT WHOSE SIGNIFICANCE IS EXEMPLIFIED BY COVID VACCINES. IMPORTANTLY, BEYOND XOLACTA, TINY CARGO'S INNOVATIVE MEV ISOLATION METHOD AND ESTER-BASED DRUG LOADING APPROACH PROVIDE A TRUE PLATFORM FOR ORAL SYSTEMIC DELIVERY OF OTHER THERAPEUTIC AND NUTRACEUTICAL MOLECULES BY MEVS. OUR DRUG IS A NOVEL ESTERIFIED COMPOSITION CALLED ACT11-4OME BASED ON THE CT-MOST 9 AMINO ACIDS OF GAP JUNCTIONAL CX43, A THERAPEUTIC THAT HAS SHOWN CLINICAL EFFICACY WHEN APPLIED TOPICALLY TO RADIATION BURNS IN CLINICAL TESTS. TINY CARGO HAS COMPLETED SUCCESSFUL STUDIES WHEREIN ORALLY ADMINISTERED XOLACTA PROTECTED HEALTHY TISSUES FROM THE EFFECTS OF THERAPEUTIC (7 GY) IONIZING RADIATION. IMPORTANTLY, WHILST NORMAL TISSUES WERE PROTECTED DURING RT, GL261 ABDOMINAL TUMORS WERE NOT PROTECTED FROM RADIATION. INDEED, ANIMALS GIVEN BOTH RADIATION THERAPY (RT) AND XOLACTA SAW NO INCREASE IN TUMOR SIZE FROM THOSE WHO RECEIVED RT ALONE. THESE LANDMARK RESULTS HAVE LED US TO EXPAND OUR CANCER TREATMENT REGIMEN TO INCLUDE CLINICALLY APPROPRIATE HER2 CANCER MODELS, SUCH AS THOSE UTILIZED BY OUR ACADEMIC COLLABORATOR, DR. ELIZABETH YEH. IN THIS APPLICATION WE PROPOSE TO ADVANCE XOLACTA AS AN ADJUVANT THERAPY TO TREAT THE SIDE-EFFECTS OF RADIATION DURING TREATMENT OF HER2 CANCER, ENABLING IND SUBMISSION TO THE FDA AS AN ADJUVANT THERAPEUTIC. OUR PRELIMINARY RESULTS INDICATE THAT XOLACTA PROTECTS GI AND BONE MARROW TISSUES FROM THE EFFECTS OF RADIATION, WHILE NOT PROTECTING TUMORS FROM RADIATION. WE ALSO HAVE PRELIMINARY DATA INDICATING THAT UPTAKE OF MEVS IN IRRADIATED TISSUES IS INCREASED OVER NON-IRRADIATED TISSUES, INCLUDING THE BRAIN. BUILDING ON THESE RESULTS, TINY CARGO SEEKS TO: 1) TEST THE EFFICACY OF XOLACTA IN TREATING HER2 BREAST CANCER WITH AND WITHOUT STANDARD OF CARE TREATMENTS FOR HER2 BREAST CANCER INCLUDING RT AND HER2-TARGETED INHIBITORS; AND, 2) DETERMINE THE SAFETY OF XOLACTA DURING RT TREATMENT FOR CANCER IN A VETERINARY CLINICAL TRIAL IN COMPANION ANIMAL PATIENTS AT THE ANIMAL CANCER CARE AND RESEARCH CENTER AT THE VIRGINIA MARYLAND COLLEGE OF VETERINARY MEDICINE. IN PREPARATION FOR CMC ADHERENCE UNDER FDA REQUIREMENTS, WE WILL PRODUCE XOLACTA AS A PHARMACEUTICAL-GRAD THERAPEUTIC IN A PURPOSE BUILT GMP FACILITY IN ROANOKE, VA. SUCCESSFUL COMPLETION OF THESE AIMS WILL ENABLE IND SUBMISSION TO THE FDA TO GAIN APPROVAL FOR ENTRY INTO CLINICAL TESTING OF ORALLY ADMINISTERED XOLACTA AS A DUAL-USE ADJUVANT THERAPY DURING RT TREATMENT OF HER2 BREAST CANCER.